Despite years of research into the development of new methods of treatment, cancers of the lymphoid system, lymphomas and certain leukemias, remain quite common. For example, more than 63,000 people in the United States are diagnosed with lymphoma each year, including more than 56,000 cases of non-Hodgkin's Lymphoma (NHL). In addition, there are about 10,000 cases of chronic lymphocytic leukemia (CLL) and 4000 cases of acute lymphocytic leukemia (ALL) diagnosed in the United States each year. Approximately 85% of the NHL, CLL, and ALL cases as a group are derived from B lymphocytes. The prognosis for those affected by these diseases is often poor, as the survival rates for lymphoma patients remain low. New methods for treating these diseases are needed.
While traditional treatments for lymphoma typically depend on the type of lymphoma as well as the medical history of the patient, first-line treatment for many lymphomas typically includes chemotherapy. Such chemotherapy will often entail the administration of a “cocktail” of compounds, e.g., the formulation CHOP, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone. In addition, certain first-line cancer treatments also include other forms of cancer therapy, such as radiation or antibody therapy. In many cases, patients respond initially to such first-line treatments, but subsequently suffer a relapse, i.e., a tumor reappears or resumes growing. Following one such relapse, patients are often treated with further chemotherapy, e.g., with CHOP or with other formulations, or, in some cases, the patients are treated with other procedures such as bone marrow transplantation.
Antibody therapies take advantage of the fact that lymphoid cells express cell surface markers that are restricted to specific lymphoid cell types. For example, the antibody most frequently used for the treatment of B cell-derived lymphomas and leukemias, Rituxan, specifically binds to CD20, which is restricted in its expression to B lymphocytes. Rituxan is used as a naked antibody and effectively depletes both normal and cancerous B cells. Rituxan has been approved for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL), in which scenario it has shown a response rate of about 50% and a median duration of response, defined as progression free survival, of about 1 year. Rituxan has also been approved for the first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin's lymphoma (DLBCL-a type of NHL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens. In this scenario, the addition of Rituxan extends progression free survival over that seen with chemotherapy alone by about 1.5 years. Multiple mechanisms of action are thought to contribute to Rituxan's cytotoxic effect, including antibody dependent cellular cytotoxicity and complement dependent cytotoxicity. The long residence time of CD20 on the cell surface and its resistance to internalization following antibody binding contribute to the ability of Rituxan to focus these natural immune functions on the cancer cell.
The success of Rituxan has spurred multiple drug development programs focused on CD20. Two radiolabelled antibodies specific for CD20, Zevalin and Bexxar, are already on the market. Several companies have new CD20-specific antibodies in clinical development. Antibody mimetics targeting CD20 are also in various stages of development. While future CD20-specific biologics may provide further improvement in response rate and duration of response over those attained with Rituxan, it is nearly certain that there will still be many patients who do not respond at all to CD20-targeted therapy or who will require a different class of drugs following relapse.
CD22 is another surface molecule restricted in its expression to B lymphocytes. CD22 is expressed in 60-80% of B cell malignancies. Naked antibodies and radiolabelled antibodies have shown encouraging results in treating NHL, either as monotherapy or in combination with chemotherapeutics or Rituxan. Further, the fact that CD22, unlike CD20, readily internalizes following antibody binding has opened the door to the development of immunotoxins, antibodies that are conjugated to toxic moieties that are released once inside the target cell. While immunotoxins are often very potent, they frequently cause undesirable toxicities, including death. The toxicities seen with immunotoxins are thought to derive in large part from extracellular release of the toxins.
Mantle cell lymphoma is an example of an aggressive, non-Hodgkins lymphoma. Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). Mantle cell lymphoma is generally characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein. Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease. However, the median survival is significantly shorter (3-5 years) than that of other lymphomas; hence this histology is now considered to be an aggressive lymphoma.
Drugs that specifically target B lymphocytes are also candidate therapeutics for the treatment of autoimmune diseases. Most notably, Rituxan has been approved for the treatment of rheumatoid arthritis. Additional anti-CD20 antibodies and antibody mimetics as well as biologics targeting CD22 are also likely to be effective in treating rheumatoid arthritis as well as other autoimmune diseases.